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J Neurosci. 2019 Jan 9. pii: 2443-18. doi: 10.1523/JNEUROSCI.2443-18.2018. [Epub ahead of print]

Loss-of-huntingtin in medial and lateral ganglionic lineages differentially disrupts regional interneuron and projection neuron subtypes and promotes Huntington's disease-associated behavioral, cellular and pathological hallmarks.

Mehler MF1,2,3,4,5,6,7,8,9,10, Petronglo JR1,2,3,6, Arteaga-Bracho EE1,2,3,6, Gulinello M4,6, Winchester ML1,2,3,6, Pichamoorthy N1,2,3,6, Young SK1,2,3,6, DeJesus CD1,2,4,6, Ishtiaq H1,2, Gokhan S1,2,3,6, Molero AE11,2,3,6.

Author information

1
Roslyn and Leslie Goldstein Laboratory for Stem Cell Biology and Regenerative Medicine, Albert Einstein College of Medicine, Bronx, NY, USA.
2
Institute for Brain Disorders and Neural Regeneration, Albert Einstein College of Medicine, Bronx, NY, USA.
3
The Saul R. Korey Department of Neurology, Albert Einstein College of Medicine, Bronx, NY, USA.
4
Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY, USA.
5
Department of Psychiatry and Behavioral Sciences, Albert Einstein College of Medicine, Bronx, NY, USA.
6
Rose F. Kennedy Center for Research on Intellectual and Developmental Disabilities, Albert Einstein College of Medicine, Bronx, NY, USA.
7
Einstein Cancer Center, Albert Einstein College of Medicine, Bronx, NY, USA.
8
Ruth L. and David S. Gottesman Institute for Stem Cell Biology and Regenerative Medicine, Albert Einstein College of Medicine, Bronx, NY, USA.
9
Center for Epigenomics, Albert Einstein College of Medicine, Bronx, NY, USA.
10
Institute for Aging Research, Albert Einstein College of Medicine, Bronx, NY, USA.
11
Roslyn and Leslie Goldstein Laboratory for Stem Cell Biology and Regenerative Medicine, Albert Einstein College of Medicine, Bronx, NY, USA aldrin.molero@einstein.yu.edu.

Abstract

Emerging studies are providing compelling evidence that the pathogenesis of Huntington's disease (HD), a neurodegenerative disorder with frequent midlife onset, encompasses developmental components. Moreover, our previous studies using a hypomorphic model targeting huntingtin during the neurodevelopmental period indicated that loss-of-function mechanisms account for this pathogenic developmental component (Arteaga-Bracho et al., 2016). In the present study, we specifically ascertained the roles of subpallial lineage species in eliciting the previously observed HD-like phenotypes. Accordingly, we used the Cre-loxP system to conditionally ablate the murine huntingtin gene (Httflx) in cells expressing the subpallial patterning markers, Gsx2 (Gsx2-Cre) or Nkx2.1 (Nkx2.1-Cre) in Httflx mice of both genders. These genetic manipulations elicited anxiety-like behaviors, hyperkinetic locomotion, age-dependent motor deficits and weight loss in both Httflx;Gsx2-Cre and Httflx;Nkx2.1-Cre mice. In addition, these strains displayed unique but complementary spatial patterns of basal ganglia degeneration that are strikingly reminiscent of those seen in human cases of HD. Furthermore, we observed early deficits of somatostatin+ and Reelin+ interneurons in both Htt subpallial null-strains, as well as early increases of cholinergic interneurons, Foxp2+ arkypallidal neurons, and incipient deficits with age-dependent loss of parvalbumin+ neurons in Httflx;Nkx2.1-Cre mice. Overall, our findings indicate that selective loss-of-huntingtin function in subpallial lineages differentially disrupts the number, complement and survival of forebrain interneurons and globus pallidus GABAergic neurons, thereby leading to the development of key neurological hallmarks of HD during adult life. Our findings have important implications for the establishment and deployment of neural circuitries and the integrity of network reserve in health and disease.SIGNIFICANCE STATEMENTHD is a progressive degenerative disorder caused by aberrant trinucleotide expansion in the huntingtin gene. Mechanistically, this mutation involves both loss- and gain-of-function mechanisms affecting a broad array of cellular and molecular processes. Although huntingtin is widely expressed during adult life, the mutant protein only causes the demise of selective neuronal subtypes. The mechanisms accounting for this differential vulnerability remain elusive. In this study, we have demonstrated that loss-of-huntingtin function in subpallial lineages not only differentially disrupts distinct interneuron species early in life, but also leads to a pattern of neurological deficits that are reminiscent of HD. This work suggests that early disruption of selective neuronal subtypes may account for the profiles of enhanced regional cellular vulnerability to death in HD.

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